In the prior art, most medications are administered by “classical”, systemic methods. Common examples are oral intake, gastrointestinal discharge, inhalation, syringe injection to muscles or blood vessels and others. For treatments of a specific organ ailment, most of the drug material released by these “classical” methods is wasted. It is blocked, washed away and destroyed before reaching its designated target. In most cases, only an extremely small fraction of the administered medication finally reaches the desired destination.
These old fashioned methods are not just wasteful. Quite frequently, systemic drug administration entails harmful side-effect risks, e.g., damage to normally functioning organs, destructive interference with normal body functions, or drug addiction with severe long term dependence.
In response, the pharmaceutical industry is investing large resources, trying to develop new schemes of controlled drug release. These R & D efforts address the issues of targeting, timing and efficiency of pharmaceutics discharge. Implantable, controlled drug delivery units are extensively pursued as well.
Slow-release pharmaceutics capsules are widely used nowadays. A single intake is involved. Drug discharge is effective over lengthy periods, yet with ever diminishing diffusion rates. In most cases systemic drugs are involved, occasionally carrying risks of side effects. The scientific and technological issues associated with this type of drug administration are still under intense R & D efforts.
Recent efforts to develop slow-release, targeted, passive devices have met success, specifically with arterial stent implants. Thin coatings of special matrices storing bioactive agents found success in preventing restenosis or local infections. The storage capacity of the coating is very limited and operation time is restricted to 30-60 days. Yet, the therapeutic effectiveness, notwithstanding the minute doses of discharged drug, is impressive.
Another prominent technique, under considerable R & D efforts, uses various types of pumps, some without moving mechanical elements. External or implanted pumps are used for fluidic drug administration. Coupled to electronic units they offer good control of release rate and duration, spanning long operational periods. The drug reservoir of an implanted pump could be replenished periodically. However, drug discharge is systemic.
Pumps with no moving parts are also under intensive R & D efforts. Some pumps use electro-osmosis force to drive electrolytes in micron sized channels. In essence, the architecture is an adaptation of capillary electrophoresis devices.
Other novel ideas pertaining to drug release systems are widely pursued. One class relates to single-time operation capsules, with coupling to an external power source that radiates energy to the capsule cap. Absorbed energy brings cap rupture, followed by drug dispensation. The directed energy is in the form of ultrasonic waves or laser beams transferred by fiber optics to the capsule cap. Cap temperature rises due to the absorbed ultrasound or laser radiation, resulting in cap disintegration. Such capsules can be implanted at the most effective locations. With this scheme, timing and location are effectively controlled, but the dose rate and integrated dose are fixed a priori. Since drug release is indeed local, a small total dose is conceivable. Examples include ultrasonic driven capsules and laser activated units. Laser activated capsules need a fiber optic connection for laser-energy transfer to the device.
Other investigators suggest microchips for drug storage and local release on command. The microchips are typically processed by MEMS technology on silicon substrates. The microchips contain chemically etched micro-channels, where drugs, or drug combinations, are subsequently stored. Drug release is initiated by an electrical signal. In some models, a high current signal heats the microchip and either activates the drug itself or induces damage to the enclosure cap that opens a route to medication outflow. Various schemes of microchip activation are offered. In one version, molecules diffuse freely and release rate is controlled by selection of cap material. In another embodiment, the cap disintegrates on application of an electric current. Another option is electrochemical activation at the cap, followed by cap degradation. Yet another version offers electric-field activated ion-exchange, resulting in cap disintegration.
Laboratory size electrophoresis devices have been suggested for controlled drug delivery. The device is external to the patient body. Drug discharge is transdermal, thus sharing shortcomings inherent to “classical” delivery methods.
Another controlled drug administration method uses an electric field applied on blood vessels, enhancing either drug or gene penetration into blood cells (electroporation process). Electric fields of order 0.2-20 kV/cm drive the electroporation process. High voltage is required to produce effective electric-fields of this magnitude on a regular blood vessel. In line with this idea, release of tumor-killer agents, encapsulated in non-permeable liposome, has been suggested. Strong electric-fields will force electroporation, delivering the toxic agent at a specific location, hence bypassing full body exposure.
Electrophoresis devices have become the universal tool for separation and identification of large organic molecules. The most common application at present is DNA separation and genome mapping. Separation is based on mobility variation between charged molecules subjected to an applied electric field. Electric fields in the order of 50V/cm are typical to this method. Since, in most cases, the length of the electrophoresis device is measured in tens of centimeters, the applied voltage is in the order of kilovolts.
The electrophoresis device is loaded with gel material. The gel forms narrow, twisting pores confining the molecular motion. Surface effects from gel walls are extremely important in determining the molecular flow. Effective charge state and drag forces are controlled by gel surface effects. The molecular drift path is contorted, becoming significantly extended relative to the instrument length. Molecular drift is slowed down considerably. Molecular-mass differentiation is obtained effectively over large distances and the process is time consuming.
In recent years, miniaturization of the laboratory size electrophoresis devices has taken place at an accelerated pace. Capillary electrophoresis systems are the result of these efforts. Narrow mechanical capillary channels, sized similar to gel pores, are the retarding medium.
The capillary electrophoresis devices have the benefits of lower bias voltages, increased molecular velocities, and short separation times. Electric fields of over 200V/cm are common, inducing faster molecular drifts. The miniaturization efforts had an impressive impact on the race to genome mapping, resulting in genome mapping periods much shorter than originally envisioned.
Electrophoresis devices were harnessed to drug delivery during the last 15 years. Laboratory size devices were suggested with transdermal administration. However, the method did not receive much demand. The presence of a high voltage bias is not entirely friendly to the human environment.
As regards size, even capillary electrophoresis systems are too big to serve as implanted drug delivery units. Indeed, the capillaries are small in diameter, in the order of 50 micrometers, but their length varies from 50-500 millimeters.